Journal Article

DKFZ-2025-00914

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Selection of therapeutically effective T-cell receptors from the diverse tumor-bearing repertoire.

Rosenberger, L. ; Hansmann, L. A.DKFZ* ; Anastasopoulou, V.DKFZ* ; Wolf, S. P. ; Drousch, K. ; Moewes, C. ; Feng, X. ; Cao, G. ; Huang, J. ; Yew, P. Y. ; Strønen, E. ; Kato, T. ; Saligrama, N. ; Olweus, J. ; Nakamura, Y. ; Willimsky, G.DKFZ* ; Blankenstein, T. ; Schreiber, H. ; Leisegang, M.DKFZ*

2025
BioMed Central London

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Please use a persistent id in citations: doi:10.1136/jitc-2024-011351

Abstract: The development of T-cell receptor (TCR)-based T-cell therapies is hampered by the difficulties in identifying therapeutically effective tumor-specific TCRs from the natural repertoire of a patient's cancer-specific T cells.Here, we mimic experimentally near-patient conditions to analyze the T-cell repertoire in euthymic tumor-bearing mice responding to the H-2Kb-presented neoantigen p68S551F (mp68). We temporarily separated the time point of mp68 expression from that of cancer cell transplantation to exclude the influence of injection-induced inflammation on T-cell priming. Thus, the mp68-specific T-cell response could only develop after the acute inflammatory phase had subsided.We found that mp68-specific TCRs isolated from either tumor-infiltrating T cells or spleens of mice immunized with mp68-expressing cancer cells are diverse and not inherently therapeutic when introduced into peripheral T cells and used for adoptive therapy of established tumors. While measuring short-term T-cell responses in vitro was unreliable for some TCRs in predicting their therapeutic failure, assessing the persistence of cancer cell destruction by TCR-modified T cells in long-term cultures accurately predicted therapeutic outcomes. A tumor-derived TCR with optimal function was also correctly identified with this approach when analyzing human TCRs that recognize the HLA-A2-presented neoantigen CDK4R24L.We show that a neoantigen-directed T-cell response in tumor-bearing hosts comprises a diverse repertoire. Infiltration and expansion of certain T-cell clonotypes in the tumor do not necessarily correlate with therapeutic efficacy of their TCRs in adoptive therapy. We propose that analysis of persistent rather than immediate responses of TCR-modified T cells in vitro serves as a reliable parameter to identify TCRs that are therapeutically effective in vivo.

Keyword(s): Animals (MeSH) ; Receptors, Antigen, T-Cell: immunology (MeSH) ; Receptors, Antigen, T-Cell: metabolism (MeSH) ; Receptors, Antigen, T-Cell: genetics (MeSH) ; Mice (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Humans (MeSH) ; T-Lymphocytes: immunology (MeSH) ; Antigens, Neoplasm: immunology (MeSH) ; Cell Line, Tumor (MeSH) ; Neoplasms: immunology (MeSH) ; Neoplasms: therapy (MeSH) ; Adoptive cell therapy - ACT ; Immunotherapy ; T cell ; T cell Receptor - TCR ; Tumor infiltrating lymphocyte - TIL ; Receptors, Antigen, T-Cell ; Antigens, Neoplasm

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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